Vinblastine* in Neoplastic Diseaset

MIDWEST COOPERATIVE CHEMOTHERAPY GROUPS

COMMITTEE FOR THIS STUDY: THOMAS L. WRIGHT, JOHN IIURLEY, DONALD R. KORST, RAYMOND W. Mo@ro, ROBERT J. RORN, JOHN J. WILL, AND JOHN Loms

SUMMARY In a cooperative study by members of the Midwest Cancer Chemotherapy Group, @65patients with neoplastic disease were treated with vinblastine to determine its spectrum of activity as an antineoplastic drug. The best and most frequent responses were obtained in patients with Hodgkin's disease, often after they were refractory to currently available modes of therapy. Patients with other types of neoplastic disease occasionally obtained worth-while objective responses with this agent, but these occurred infrequently. VLB is a relatively safe oncolytic agent when used with proper precautions. The dose is variable, and it is suggested that the optimum therapeutic dose is that quantity which will produce mild leukopenia without severely depressing the bone marrow or inducing other side effects. Recovery from leukopenia is usually prompt except with the severest toxicity.

In a cooperative study by the members of the Vinblastine is an alkaloid of the common pen Midwest Cancer Chemotherapy Group a series of winkle, Vinca rosea Linn, and represents a new @65patients was treated with vinbiastine (VLB, class of oncolytic agents. During pharmacologic Vincaleukoblastine, and Velban) to determine its investigation (14, 15) it was noted that granulo spectrum of activity as an antineoplastic drug TABLE 1 (Table 1). iNSTITUTIONS CONTRIBUTING CASES TO VLB STUDY * Vinblastine is the generic name assigned to Vincaleuko blastine. t A preliminary report of this study was presented at the casesCleveland InstitutionNo. American Association for Cancer Research, April, 1961. Ohio4Cook Clinic, Cleveland, @ Supported by the following research grants from the Can illinois7HenryCounty Hospital, Chicago, cer Chemotherapy National Service Center, National Cancer Michigan82IndianaFord Hospital, Detroit, Institute, Public Health Service, U.S. Department of Health, University, Indianapolis, indiana Education, and Welfare: CYP 4919—Cleveland Clinic (Battle, Marquette University, Milwaukee, Wisconsin 82 8Presbyterian—St.Ohio State University, Columbus, Ohio96* J., Hewlett, J.); CYP 4913—HektoenInstitute (Schwartz, Luke's Hospital, Chicago, S.); CYP 4915—Henry Ford Hospital (Monto, R., Rebuck, illinoisIUniversity J.); CYP 4921—MarquetteUniversity (Pisciotta, A.); CYP Ohio19Universityof Cincinnati, Cincinnati, 4920—Ohio State University (Doan, C., Wall, R., Wilson, H., Illinois9Universityof Illinois, Chicago, Bouroncle,B.); CYP 5429—Presbyterian—St.Luke'sHospital Iowa15V.A. of Iowa, Iowa City, (Trobaugh, F.); CYP 4914—UniversityofCincinnati (Will,J., Wisconsin12V.A.Center, Wood, Vilter, R.); CYP 4912—University of illinois (Louis, J., Chair Michigan28V.A.Hospital, Ann Arbor, man, Best, W., Limarzi, L); CYP 4916—IndianaUniversity Research Hospital, Chicago, Illinois2Total: (Rohn, R., Bond, W.); CYP 4917—University of Iowa 265 (Fowler,W.); CYP4938—UmversityofMichigan(Bishop,R., Zarafonitis, C.); CYP 4918—Wayne State University (Clif ford, G.); V. A. Center, Wood, Wisconsin (Dessel, B.); V.A. *27 of these cases have been reported previously (10). Hospital, Ann Arbor, Michigan (Korst, D., Frenkel, E.); V.A. Hospital, Minneapolis,Minnesota (Hagen, P.); Veterans Ad cytopenia was produced in experimental animals ministration, Washington, D.C. (Lee, L); V.A.R. Hospital, and that the material possessed definite cytostatic Chicago, Illinois (Unman, J.). activity against transplantable mammary adeno Received for publication May 28, 1962. carcinoma in DBA/Jax mice and against a trans 169

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plantable sarcoma in the rat. The alkaloid respon considered to have received an inadequate trial on sible for these effects was crystallized and named the drug. Of the 77 patients excluded from study, Vincaleukoblastine (14). 63 did not survive for 14 days and were considered Preliminary clinical trials (9) indicated that to have had terminal disease. The remaining four VLB possessed some degree of antineoplastic ac teen patients in this group were not evaluated for a tivity, and this study was accomplished to define variety of reasons, including loss to follow-up, con better the response of a wide variety of neoplastic comitant therapy with another antineoplastic diseases to this agent. agent, and refusal of further therapy by the pa tient. MATERIALS AND METHODS All patients had advanced neoplastic disease RESULTS confirmed by tissue biopsy. The types of neoplastic Toxicity.—The types and incidence of toxicity disease studied are shown in Table @. are tabulated in Table 3. An incidence of 35 per The VLB was supplied as a dry, sterile powder cent leukopenia of less than @,000WBC/cu mm in ampules containing 10 mg. The drug was dis reflects the fact that some degree of leukopenia solved in sterile water, 5 per cent dextrose in Wa was sought in every case as an indication of ade ter, or physiologic saline, and given, except where quate dosage of the drug. Thrombocytopenia of specifically noted, into the rubber tubing of an in less than 100,000 platelets/cu mm was associated travenous infusion of physiologic saline. In out with the leukopenia in only two instances. Pa patients VLB was injected directly into veins in a tients with leukopenia usually recovered within concentration of 1 mg VLB/@ ml saline. 1-@ weeks. Nine patients had agranulocytosis, Drug administration.—Initially most of the pa which was considered a contributing cause of tients were treated with 0.10—0.15 mg/kg of body death. Three of these had had prior therapy with weight for 1, @,or3 days. In this report the total alkylating agents, two with 5-fluorouracil, and one dose given in the first 3 days of therapy has been with local radiation therapy. The total dose associ defined as the priming dose. Subsequent doses ated with agranulocytosis varied from 0.30 to 1.1 were increased or decreased to induce mild leuko mg/kg (mean, 0.54). Eight of these deaths oc penia, and in general were not administered until curred within 14 days of the onset of therapy. there had been some reversal of leukopenia in Gastrointestinal toxicity was prominent, and 11 duced by a previous dose. per cent of the patients reported nausea and 5 per An alternate schedule was to begin at a dose of cent vomited after the injection of VLB. Stomati 0.10 mg/kg and then to increase in increments of tis was the toxic manifestation of next greatest 0.05 mg/kg every 4—7days until toxicity or benefit frequency. Changes in gastrointestinal tract mo appeared. Maintenance therapy was then given, tility occurred in 6 per cent of the patients, and in usually weekly or biweekly at a level that just six patients a paralytic ileus developed which in avoided the production of toxicity. one case lasted for 7 days. Hemorrhagic enterocoli Criteria of evaluation.—The criteria for the tis was found at post-mortem examination in one evaluation of therapeutic response were defined as patient after treatment with VLB without con follows: comitant antibiotic therapy. 1. Complete remission. No evidence of disease Some degree of epilation occurred in 54 per in all parameters of measurement. cent. Phlebitis in five patients and necrosis in two @.Objective improvement. Improvement in a patients occurred at the injection site in spite of measurable parameter, either physical or labora the precautions taken in giving the medication. tory, which could not be attributed to the natural Transient pain at the site of the primary tumor im history of the disease, supportive therapy or prior mediately after the injection of VLB occurred in treatment. four patients, all of whom had carcinomas of the 3. Subjective improvement. Improvement in head and neck. symptomatology or performance status, without Neurological manifestations occurred in 9 per any improvement in physical or laboratory param cent of the patients. The commonest was some de eters capable of objective measurement. gree of lethargy and depression, and in two pa 4. No response. Patient remained unchanged or tients confusion lasting for approximately 48 hours demonstrated progression of the disease while un appeared to be related to VLB. In other patients der therapy. absence of deep tendon reflexes and paresthesias of Patients who for any reason could not be stud the hands and feet were noted, and two patients ied for a minimum of 14 days after the onset of experienced more severe transient peripheral therapy were not evaluated, because they were neuritis.

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1963 American Association for Cancer Research. TABLE 2 TUMOR RESPONSE TO VLB

tive im dose dose of therapy TumorObjective improve evalu prove responseNot (mg/@cg)*Maintenance mentSubjec aPriming (mg/kg)Duration (days) mentNo

Hodgkin'sDisease 12 3 6 6 0.80 1.0 74 (0 . 12—0.60) (0 08—3.40) (4—250)

Lymphosarcoma 1 0 7 2 0 .27 0 .48 19 (0.13—0.45) (0.0—0.82) (2—55) Reticulum-cell Sarcoma S 0 2 2 0 .31 0 .64 46 (0.27—036) (0.18—1.39) (15—75)

MycosisFungoides 0 0 1 0 0.20 0.66 70

Leukemia, Acute: Monoblastic 2 1 12 9 0.26 0.76 23 (0.10—0.47) (0.0—3.2) (2—72) Lymphoblastic 1 0 3 2 0.31 1.18 25 (0.10—0.50) (0-16—3.25) (10—58) Myeloblastic 1 0 2 1 0.32 0.42 15 (0 .20—0.46) (0 .33—0.48) (4—33)

Leukemia, Chronic: Lymphocytic 1 0 0 4 0.10 1.84 82 Granulocytic 0 0 3 1 0.35 0.73 10 (0.1—0.5) (0.0—1.0) (1—20)

Multiple Myeloma 0 0 2 1 (0 . 125-0 . 17) 0 . 17 (1—14)

Bronchus: Squamous 2 1 7 2 0.35 0.69 23 (0.2—0.6) (0.0—1.4) (3—57) Adenocarcinoma 1 1 1 S 0.27 0.92 25 (0.1—0.41) (0.41—1.7) (8—41) Undifferentiated 1 0 0 0 0.30 1.4 226 Oat-cell 1 0 0 1 0.30 0.5 26 Not specified 0 1 5 4 0.29 0.89 19 (0.15—0.4) (0.15—0.67) (7—46)

Breast: Adenocarcinoma 0 0 7 1 0.25 0.31 22 (0.15-0.45) (0.0—0.90) (3—99) Esophagus: Squamous 0 1 0 0 0.43 0.15 17

Stomach: Adenocarcinoma 0 0 1 4 0.80 0.15 9

Colon and Rectum: Adenocarcinoma 2 3 8 7 0.27 1.15 50 (0.15—0.48) (0.0—5.40) (2—117)

Pancreas: Adenocarcinoma 0 3 1 1 0.40 0.70 44 (0.21—0.57) (0.47—1.08) (14—76) Undifferentiated 1 0 0 0 0 -10 0 .85 49

Liver: Hepatoma 1 0 1 2 (0.3-0.3) (0.26—0.44) (5—17)

Prostate: Adenocarcinoma 0 4 3 1 0.27 0.57 77 (0 . 16—0.40) (0 . 15—0.80) (16—200)

Kidney: Adenocarcinoma 0 3 0 1 0 .5 1 .07 55 (0.3—0.6) (0.42—2.9) (30—95) Hypernephroma 0 1 1 1 (0.2—0.4) (0.0—16) (3—59) Bladder and Ureter 0 1 1 1 (0.3-0 .3) (0.2—0.90) (8—179)

* Mean value, with range given in parentheses.

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TABLE 2—Con@inurd

tive in dose dose of therapy TumorObjective improve evalu prove responseNot (mg/@)*Maintenance (days) mentSubjec atelPriming (mg/kg)Duration mentNo

Uterus: Adenocarcinoma 1 0 1 0 (0.15—0.2) (0.35-0.35) (66—22) Squamous 0 3 1 2 0.40 0.34 20 (0.15-0.6) (0.18—0.77) (4—58)

Ovary: Adenocarcinoma 1 1 5 2 0.27 0.91 33 (0.15—0.40) (0.0—2.7) (1—75)

Skin: Squamous 2 0 0 2 (0.30—0.43) (0.43—1.0) (47—55)

Tongue Squamous 1 0 0 1 0.30 0.30 11

Larynx: Squamous 0 4 1 0 0.43 0.35 31 (0.35-0.55) (0.12—0.55) (20-40)

Undetermined Primary Site: Squamous 0 0 2 0 (0.20—0.30) (0.60-0.80) (44—53) Adenocarcinoma 0 0 3 0 0.31 0.36 32 (0.13—0.49) (0.12—0.63) (9—57) Undifferentiated 0 0 5 1 0.18 0.69 12 (0.10-0.31) (0.0—1.88) (2—26)

Melanoma: Skin 0 1 5 3 0.23 0.57 24 (0.10-0.4) (0.22—1.00) (13—32) Retina 1 2 0 0 0.36 0.69 98 (0.20—0.47) (0.62—0.75) (30—135)

Sarcomas 0 1 7 5 0.27 0.52 45 (0.10—0.4) (0.10—1.41) (13—150)

Other: Testis,embryonal-cell 1 0 0 2 0.30 0.30 4 Ependymoma 0 0 1 0 0.35 0.35 6 Astrocytoma 0 0 1 0 0.20 0.40 21 Glioblastoma 0 1 1 0 (0.3 —0.37) (0.12—0.74) (45-47) Meduloblastoma 0 1 1 0 (0.32—0.45) (0.0—0.75) (2—39) Sympathicoblastoma 0 0 1 0 0.23 0.61 53 Paraganglioma 0 1 0 0 0.20 0.83 59 Retinoblastoma 1 0 0 0 0.36 1.43 47 Malignant Schwannoma 0 0 1 0 0.38 0.0 1 Skin, basal-cell 0 0 1 1 0.30 0.0 1 Penis, squamous 1 0 0 0 0.10 1.50 34 Thyroid, adenocarcinoma 0 0 0 1

Therapeutic results.—The over-all tumor re provement following the institution of VLB ther sponse to VLB is summarized in Table @.Of @65 apy but did not improve in any measurable param patients placed on study, 188 were considered to eter. Most commonly this was some degree of pain have had adequate evaluations. No patient had a relief, often associated with decreasing narcotic complete remission. Thirty-nine patients had ob requirements and sometimes with increasing per jective improvement which, unfortunately, was formance status. These have been tabulated in not equated in every instance with significant ben Table @. efit to the patient, a more difficult parameter to Hodgkin's disease.—The condition most respon evaluate. Therefore, in Table 4 the exact objective sive to treatment was Hodgkin's disease. All but improvement and the character of the subjective four of the patients had prior therapy with an improvement which occurred in each patient are alkylating agent, and many had received local indicated. radiation therapy. Twelve patients obtained oh A number of patients reported subjective im jective improvement lasting from 13 to @14days.

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@ However, in two it lasted only weeks and was leukocyte count, but no other signs of improve associated with little subjective improvement ment. (Table 4, Cases 11 and I @).Four of the twelve pa Carcinoma of lung or bronchus.—Thirty-one pa tients showed minimal tumor regression but good tients were studied, of whom @1were evaluated. symptomatic improvement (Table 4, Cases 5, 8— All but four patients had received prior therapy 10), and these remissions tended to be of short with x-ray, alkylating agents, or 5-fluorouracil. duration (13—35days), with one exception of @14 Five patients showed objective improvement of days. In the remaining six patients there was a short duration (921—48days), but one patient with good correlation between the objective and subjec undifferentiated carcinoma showed marked regres tive improvement observed (Table 4, Cases 1—4,6, sion of a right hilar mass, which, on maintenance 7) . Most of the patients were observed to relapse therapy, was sustained for @215days (Table 4, Cases while on maintenance therapy, but a second par @—@6).Itis of interest that four histologic types of tial remission could be obtained occasionally with retreatment if maintenance therapy had been pre TABLE 3 viously discontinued or maintained at a very low ToxIcITY IN 265 PATIENTS dose. Three patients had only subjective improve ment, which was sustained for 16, @21,and 99 days. SymptomNo. . Otherlymphoma&.—Eighteenpatients with other ageLeukopenia patientsPercent types of lymphomas were placed on study, and WBC/cumm)9034.8Thrombocytopenia(less than 2,000 fourteen of these were evaluated. Eight patients had lymphosarcoma, of whom six had prior ther (less than 100,000 mm)20.8Nausea3011.5Vomiting135.0Stomatitis93.5fleus62.3Constipation51.9Diarrhea51.9Rectalplatelets/cu apy including alkylating agents, x-ray therapy, 6- mercaptopurine, or corticosteroids. Only one pa tient showed objective improvement (Table 4, Case 13). Five patients with reticulum-cell sar coma were evaluated, of whom two had received prior therapy. Three patients obtained objective bleeding31.2Hemorrhagic regression in tumor mass (Table 4, Cases 14—16). enterocolitis10.4Epilation145.4Phlebitis Acute leukemias.—Thirty-four patients with acute leukemia were studied. F@ourpatients with acute lymphoblastic leukemia were evaluated. All at injection site Pain1.5Necrosis in primary tumor site5 41.9 had had prior therapy with folic acid antagonists site20.8Chillsat injection and corticosteroids, and one had had, in addition, injection20.8Lethargyand fever following therapy with oral VLB. Three patients with acute depression83.1Lossofreflexes72.7Paresthesiasand myeloblastic leukemia were evaluated. None had received prior therapy. Fifteen patients with acute .2Peripheral of extremities31 neuritis20.8Toxic monoblastic leukemia were evaluated. Eleven of psychosis20.8 these had had no prior therapy. All the patients who were evaluated except one obtained a fall in their leukocyte count of greater carcinoma, squamous, oat-cell, adenocarcinoma, than 50 per cent of the pretreatment level, and and undifferentiated, were included among those nine had a leukopenia of less than @,O0Oproduced with objective improvement. by therapy. In spite of the marked leukopenic ef Carcinoma of the brea,@t.—Eight patients were placed on study, and seven were evaluated. Prior feet, only four obtained oilier objective imp$ve therapy included x-ray, hormonal therapy, 5- ment from the drug (Table 4, Cases 17-420). In two fluorouracil, and alkylating agents. No improve of these four patients the improvement observed ment occurred in any patient. was of questionable importance, since it was unac Carcinoma of the gastrointestind tract.—Thirty companied by an improving performance status. five patients were studied, of whom @1were evalu Chronic leukemia.—Nine patients with chronic ated. They included thirteen with adenocarcinoma leukemia were studied, but only four were evalu of the large intestine, one with squamous carcino ated. One patient with chronic lymphatic leukemia ma of the esophagus, one with adenocarcinoma obtained shrinkage of tumor mass (Table 4, Case of the stomach, two with hepatoma, and four el). Three patients with chronic granulocytic leu with carcinoma of the pancreas. Eleven of these kemia were evaluated. All three of these patients patients had received no prior therapy; the others demonstrated a marked fall in their peripheral had been treated with local x-ray or various chem

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1963 American Association for Cancer Research. TABLE 4

OBJECTIVE RESPONSE TO VLB

Total ofNo.AgeSexDiagnosisPrior dosePenod therapyVLB (mg/ apy kg)then (days)ToxicityComments

68 F Hodgkin's disease None 1 .38 138 None Complete regression of enlarged lymph nodes, splenomegaly, and pleural effu sion, days 16—77.Subjective improve @ ment not determinable owing to chronic brain syndrome.

2 25 M Hodgkin's disease X-ray 3 .80 102 None Complete regression of enlarged lymph Uradil mustard nodes and splenomegaly, with subjective Streptovitacin improvement, days 19-138.

3 29 M Hodgkin'sdisease None 0.76 85 Leukopenia Moderate dea@ease in lymph nodes and subjective improvement, days 9-85.

4 22 M Hodgkin's disease X-ray I .28 136 None Moderate decrease in lymph nodes and Cytoxan pulmonary infiltrate with good sympto. matic improvement, days 12—136. Re lapse while on therapy.

5 24 M Hodgkin's disease X-ray I .50 155 Leukopenia Minimal decrease in adenopathy but corn Nitrogen mustard plete regression of splenomegaly with al most complete symptomatic improve ment, days 11-50, after 0.30 mg/kg. Re lapse day 51, at which time therapy of 0.20 mg/kg q 3 wk. was institUted. Pa tient without abnormal physical findings except moderate lymph-adenopathy to day 155. Rb increased from 8.3 to 18.8

6 46 F Hodgkin's disease X-ray 0.75 39 Leukopenia Moderate decrease in organornegaly with Chlorambucil partial symptomatic improvement, days 10—39. 7 40 F Hodgkin'sdisease X-ray 0 .74 14 Stomatitis Decreasein adenopathy and clearingof up TEM Nausea per extremity edema, days 19-88, at Nitrogen mustard which time had symptomatic relapse.

8 41 F Hodgkin's disease None 1 .00 70 None Good subjective response; minimal objec tive responseof decrease in breast infil trate and clearing of pleural effusion but with little change in lymphodenopathy or hepatosplenomegaly, days 35-70. Re lapse while on therapy.

9 8 F Hodgkin's disease X-ray 3 .30 127 Epilation Decrease in pulmonary infiltrate with little TEM Nausea changein organomegalybut almost corn Eponate Vomiting plete symptomatic relief, days 4-218, at Nitrogen mustard which time was placed on oral VLB.

10 46 F Hodgkin's disease Chiorambucil 2 .80 250 Leukopenia Minimal decrease in hepatosplenomegaly but correction of anemia, days 10—126. Minimal symptomatic improvement continued to day 210.

11 16 M Hodgkin's disease X-ray 0 .49 4 Nausea Complete regression in splenomegaly, days TEM 6—19,but no improvement in severe Chiorambucil symptomatology. Nitrogen mustard

12 27 F Hodgkin's disease X-ray 0 .80 11 None Marked regression in lymphadenopathy Nitrogen mustard and splenomegaly occurred; patient died died on day 14 with bronchopneumonia.

13 74 M Lymphosarcoma X-ray 1 .06 45 None Slight reduction in lymphadenopathy ac pn companied by minimal improvement in Cytoxan performance status. Prednisone

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Total ofNo.Age dosePen od therapyVLB (mg/ apy iSexDiagnosisPrior kg)then (days)ToxicityCommenti

14 69 F Reticulum-cell None 1 .09 56 Depression Complete regression of hepatosplenomeg sarcoma aly, marked decrease in lyznphadenop athy and control of bone pain asso dated with significant improvement in performance status from days 13-76, when placed on oral VLB.

15 45 M Reticulum.cell X-ray 0 .46 57 Leukopenia Minimal remission with regression in sarcoma . lymph node size and disappearance of upper extremity edema, days 13-30.

16 53 M Reticulum-cell Eponate 0 .65 15 Nausea Decrease in size of lymph nodes for 8 days sarcoma Vomiting without subjective improvement. fleus Leukopenia

17 32 F Acute monoblastic None 0 .30 2 None Complete regression of splenomegaly with leukemia symptomatic remission lasting from days 24-48. Platelets elevated from thrombocytopenic levels to normal level. Marked decrease in leukemic infiltration in bone marrow.

18 16 F Acute monoblastic 6-MP 1 .66 58 Epilation Decreasing organomegaly with marked im leukemia Steroids Leukopenia provement in performance status but no improvement in thrombocytopenia or anemia, days 4—56,at which time pa tient died with cerebral hemorrhage.

19 20 M Acute lympho. Aminopterin 0 .37 10 None Platelet count rose from markedly throm. blastic leukemia Steroids bocytopenic levels to normal, da@rs 12- Oral VLB 17, without change in physical findings or performance status.

20 3 F Acute myeloblas- None 0 .79 4 Leukopenia Complete regression of splenomegaly, days tic leukemia Diarrhea 9-18, but little improvement in perform ance status.

21 57 M Chronic lympho- TEM 2 .09 83 None Moderate decrease in hepatosplenomegaly cytic leukemia and lymphadenopathy from days 4-86.

22 75 M Bronchogenic car- None 2 .67 256 Alopecia An excellent response. Decrease in right @ cinoma, undif- hil@ associated with symptomatic ferentiated improvement sustained for 215 days, at which time progression of hilar mass was noted while still on therapy.

23 56 M Bronchogenic car- None 0 .80 26 Leukopenia Marked regression in subcutaneous metas cinoma, cat-cell tases associated with moderate clinical improvements, days 18-84.

24 44 M Bronchogenic car- X-ray I .40 38 Leukopenia Significant reduction in size of metastatic cinoma, squa- Confusion nodules in right lung fields and reaera mous tion of atelectatic left upper lobe from days, 12-55 when pulmonary embolism terminated clinical improvement.

25 32 M Bronchogenic ade- X-ray 2 .00 41 Leukopenia Decrease in pulmonary mass on x-ray, nocarcinoma 5-FU Peripheral da7s 10—58,but severe peripheral neu neuritis iitis as toxic manifestation from days 16—27.

26 70 M Bronchogenic car- X-ray 0 .47 3 Leukopenia Improvement in signs and symptoms due cinoma, aqua- ThioTEPA to cerebralmetastases from days 5-45. mous Nitrogen mustard

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Total ofNo.AgeSexDiagnosisPrior dosePen od therapyVLBthen ToxicityComments(mg/

kg)apy (days)

27 82 F Melanosarcoma, Sarcolysin 1 .09 129 Leukopenia Excellent response with almost complete retina Alopecia regression of palpable and visible tumor Ileus of faceand necklasting from days 15—60 after 0.47 mg/kg. On day 85 was given 0.31 mg/kg and again had regression of recurrent tumor but not so marked as with first treatment. On day 129 given 0.81 mg/kg but without benefit. Ther apy limited by leukopenia.

28 60 F Adenocarcinoma, 5-FU 6 .00 111 Leukopenia Excellent response with marked regression colon of large intra-abdominal masses and re lief of intestinal obstruction lasting from days 7—88.Patient relapsed while on maintenance VLB therapy.

29 64 1@4 Adenocarcinoma, Eponate 1 .74 117 Leukopenia Decrease in hepatomegaly due to extensive rectum Epilation metastases from days 16-97. Sympto Paresthe- matic improvement was minimal. sias

30 65 M Hepatoma None 0 .55 5 Leukopenia Moderate regression of massive hepato megaly without clinical benefit.

31 40 M Undifferentiated None 0 .95 49 None Complete clearing of obstructive jaundice, carcinoma, pan- decrease in size of lymph nodes contain creas . ing metastatic tumor and good pain re lief from days 14-42 followed by relapse while on therapy.

32 64 F Adenocarcinoma, X-ray 3 .00 67 Leukopenia Good control of peritoneal and pleural ef ovary Nitrogen mustard fusions for 3 months. Therapy stopped because of persistent leukopenia.

33 59 F Adenocarcinoma, X-ray 0 .50 66 Leukoperna Moderate regression in pulmonary metas endometrium Epilation tases from days 14-56 with minimal sub jective improvement.

34 73 F Epidermoid carci- X-ray 0 .85 52 Leukopenia Decrease in tumor size associated with de noma, skin of Nitrogen mustard creasing pain, days 11-48. face

35 42 M Epidermoid carci- None 1 .30 47 Leukopenia Regression of primary lesion and regional noma, skin of Nausea nodes from days 12-61 with improving face ileus performance status.

36 50 F Epidermoid carci- None 1 .20 11 None Moderate regression of primary lesion last noma, tongue ing from days 13-27.

37 29 M Embryonal-cell X-ray 0 .60 3 Nausea Complete regression of enlarged lymph carcinoma, tes- Vomiting nodes containing metastatic disease and tis Leukopenia moderate decrease in pulmonary metas Epilation tases from days 3-41 when therapy changed to oral VLB.

38 2 M Retinoblastoma X-ray 1 .79 47 Leukopenia Moderate regression of metastatic nodules, TEM days 11—32,butno subjective improve ment.

39 44 M Epidermoid carci- X-ray 1 .60 34 None Moderate regression of extensive primary noma, penis lesion with good control of pain and bleeding from days 15-47. Therapy ten minated for trial of intra-arterial infu sion of nitrogen mustard.

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@ otherapeutic agents, including alkylating agents types of tumor are recorded in Tables and 4. and 5-fluorouracil. Four patients obtained objec Three patients obtained objective improvement tive improvement (Table 4, Cases @,8—31). (Table 4, Cases 37—39). Carcinoma of the female genital tract.—Eighteen patients were studied. Thirteen were evaluated, DISCUSSION including seven patients with adenocarcinoma of Vinblastine has been shown (1, @,5,6, 8—11,16, the ovary, two with adenocarcioma of the uterus, 17) to have an oncolytic effect on malignant tu and four with squamous-cell carcinoma of the mors in humans which in some cases is significant. uterus. One patient with adenocarcinoma of the The best results have been obtained in patients ovary and one patient with adenocarcinoma of the with Hodgkin's disease (1, @,6,16, 17). The data endometrium obtained objective improvement indicate that some patients who have become re (Table 4, Cases 3@, 33). fractory to the established modalities of therapy Carcinoma of the genito-urinary tract.—Eight may respond for variable periods of time to VLB een patients with carcinoma of the genito-urinary therapy with decrease in tumor mass and/or im tract were studied, and fourteen were evaluated. provement in symptomatology. The fact that some No objective changes were seen in these patients, patients with Hodgkin's disease who are refractory but nine reported subjective benefit, most com to alkylating agents may obtain responses to VLB monly relief of bone pain. The subjective improve is exciting, but a word of caution is indicated. This ment was sustained from 13 to @O3(mean 76) days study as well as other studies has not compared on maintenance therapy. the effectiveness of VLB with established methods Carcinoma of the head and neck.—Eleven pa of treatment in early Hodgkin's disease. Until this tients were studied, eight of whom were evaluated. type of comparative study is completed VLB All the tumors were squamous-cell, two of the skin should not replace the alkylating agents or local of the face, one of the tongue, and five of the x-ray therapy in the treatment of early disease, larynx. Six of the patients had received prior ther but should be reserved for those patients in whom apy with x-ray, alkylating agents, or folic acid an the response to established therapy is unsatisfac tagonists. Three patients obtained partial regres tory. sion of their tumor (Table 4, Cases 34—36).Four The response of the other forms of lymphoma patients with carcinoma of the larynx had subjec has been much less gratifying. Only one patient, tive decrease in pain lasting 14—30days. who had reticulum-cell sarcoma, obtained tumor [email protected] carcinoma, undetermined primary 8ite. regression comparable to that seen in some of the —In thirteen patients the primary site of the car patients with Hodgkin's disease. These results cinoma was not determined. Ten were evaluated. were similar to the experiences of others reported None of these patients showed any response to recently (6, 16, 17). therapy. The results in acute leukemia were disappoint Melanoma.—Of the twelve patients studied, ing and are in agreement with the responses re nine were evaluated. Prior therapy consisted of ported in other studies (10, 16, 17). A marked fall alkylating agents in three cases and radiation ther in the peripheral leukocyte count was obtained in apy in one case. One patient with metastatic almost every case, but in only four cases in our melanosarcoma of the retina obtained remarkable series was there any other objective response to the temporary regression of her disease (Table 4, Case drug, and these incomplete remissions were of @7).Three patients obtained subjective improve short duration. ment in terms of pain relief lasting from @1to110 In solid tumors the problem of evaluating (mean 58) days. worth-while clinical response is more difficult than Sarcoma.—Thirteen patients with various his in the hematologic malignancies. Unfortunately, tologic types of sarcoma of the soft tissues were measurable tumor regression cannot be equated in studied, eight of whom were evaluated. These in every instance with benefit to the patient. Patients eluded fibrosarcomas, sarcomas of bone, rhab were seen in whom regression in tumor mass was domyosarcomas, and leiomyosarcomas. Prior ther not associated with improvement in performance apy in five patients consisted of x-ray, alkylating status, although the two as a rule were correlated. agents, actinomycin D, and 5-fluorouracil. One pa Conversely, patients were seen in whom there tient with a fibrosarcoma obtained partial relief of seemed to be improvement in well-being and per pain sustained for 143 days, although the tumor formance status, most often mediated through gradually increased in size during that period. some degree of pain relief, without any decrease in Other tumor8.—Thirteen patients with other less tumor mass. These “symptomatic-only―responses common malignancies were evaluated. Results and were seen in a wide variety of tumors, but their

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exact significance is difficult to evaluate, and they the bone marrow shows some specificity in that the may be related in some instances to a pharmaco platelets tend to be spared except with severe tox logic action of VLB on the central nervous system. icity. The most significant tumor regressions in the The mechanism of action of VLB remains un solid tumors were observed in a wide spectrum of known. It has been demonstrated that it is a diverse histologic types. They occurred in patients spindle inhibitor and, like coichicine, does not ar with melanosarcoma of the retina, adenocarcino rest the initial phase of a division but halts it at ma of the ovary, embryonal cell carcinoma of the metaphase. Unlike colchicine, this inhibition of testis, adenocarcinoma of the colon, and undiffer mitosis can be prevented with the amino acids entiated carcinoma of the bronchus. No type of tryptophan and glutamic acid (3, 4). A number of tumor responded consistently in a favorable man other metabolites involved in the pathways lead ner to VLB therapy. The lack of consistent response seems to be re ing from glutamic acid to urea and from glutamic flected in the literature, where an occasional pa acid to the citric acid cycle have been demon tient has shown response to VLB. These include, strated to reverse the effects of VLB in tissue cul in addition to our patients, three patients with ture (1@). adenocarcinoma of the stomach (5, 16), five pa REFERENCES tients with carcinoma of the breast (@,11, 16), two patients with carcinoma of the ovary (@, 5), three 1. ALPERT, L K.; [email protected], H. A.; and SCHATTEN,I. C. Pre liminary Observations with Vincaleucoblastine. Proc. Am. patients with carcinoma of the testis (16), and one A.ssoc.CancerRes.,3:204,1961. each of patients with carcinoma of the bronchus 2. ARMSTRONG, J. G.; Dvxn, R. W.; Fou@rs, P. J.; and (f), the oral cavity (5), cervix (s), bladder (1), and GAHIMER, J. E. Hodgkin's Disease, Carcinoma of the pancreas (@). This sporadic improvement may not Breast, and Other Tumors Treated with Vmblastine Sul be related entirely to drug effect and may be more fate. Cancer Chemotherapy Rept., 18:49—71, 1962. 3. Cirr'rs, J. H. The Effect of Vincaleucoblastine on Dividing closely related to the natural course of some tu Cells in Vise. Cancer lIes., 21:168—72, 1961. mors. 4. Cu'rrs, J. H.; BEER, C. T.; and NOBLE, R. L Biological All these data would seem to confirm our im Properties of Vincaleukoblastine, an Alkaloid of Vinca pression from the cases with solid tumors in the Rosea Linn, with Reference to Its Antitumor Action. Can present series that an occasional patient may oh cer Rca.,20: 1028—81,1960. 5. Fans, E. ifi; FRANzIN0, A.; SHNIDER, B. 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Thomas L. Wright, John Hurley, Donald R. Korst, et al.

Cancer Res 1963;23:169-179.

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